TSC/MTOR-associated Eosinophilic Renal Tumors Exhibit a Heterogeneous Clinicopathologic Spectrum: A Targeted Next-generation Sequencing and Gene Expression Profiling Study. (19th November 2022)

• Record Type: Journal Article
• Authors: Xia, Qiu-yuan; Wang, Xiao-tong; Zhao, Ming; He, Hui-ying; Fang, Ru; Ye, Sheng-bing; Li, Rui; Wang, Xuan; Zhang, Ru-song; Lu, Zhen-feng; Ma, Heng-hui; Wang, Zi-yu; Rao, Qiu
• Is Part Of: American journal of surgical pathology. Volume 46:Number 11(2022)
• Page Start: 1562
• Page End: 1576
• Publication Date: 2022-11-19
• Subjects: renal cell carcinoma -- TSC1/TSC2 -- MTOR -- NGS sequencing; Pathology, Surgical -- Periodicals; 617.0705
• DOI: 10.1097/PAS.0000000000001955
• Languages: English
• ISSNs: 0147-5185

Abstract

Abstract : Background: Several TSC1/2- or MTOR -mutated eosinophilic renal tumor subsets are emerging, including eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumors (EVTs) and low-grade oncocytic tumors (LOTs). "Unclassified renal tumors with TSC/MTOR mutations" ( TSC -mt RCC-NOS) do not meet the criteria for other histomolecular subtypes. Whether these tumors represent a continuum of 1 TS C/ MTOR -mutation-associated disease is unknown. Design: We evaluated the clinicopathologic and IHC profiles of 39 eosinophilic renal tumors with targeted DNA sequencing-confirmed TSC/MTOR mutations. Twenty-eight of these, plus 6 ChRCC, 5 RO, 5 ccRCC, 7 MiT RCC and 6 normal renal tissues, were profiled transcriptionally by RNA-seq. Results: The 39 cases were reclassified based on morphological and IHC features as ESC RCC (12), EVT (9), LOT, (8) and TSC -mt RCC-NOS (10). The mutation profiles demonstrated consistency; ESC RCCs (12/12) had TSC mutations, and most LOTs (7/8) had MTOR mutations. Ten TSC -mt RCC-NOSs exhibited heterogeneous morphology, arising a differential diagnosis with other renal tumors, including MiT RCC, PRCC and epithelioid PEComa. RNA sequencing-based clustering segregated ESC RCC, EVT and LOT from each other and other renal tumors, indicating expression profile-level differences. Most TSC- mt RCC-NOSs (6/7) formed a mixed cluster with ESC RCC, indicating similar expression signatures; one TSC- mt RCC-NOS with unusual biphasic morphology clustered with EVT. Conclusions: We expanded the TSC/MTOR -associated eosinophilic renal tumor morphologic spectrum, identified gene mutation characteristics, and highlighted differential diagnosis challenges, especially with MiT RCC. ESC RCC, EVT, and LOT having distinct expression profiles. TSC -mt RCC-NOS may cluster with recognized TSC/MTOR -associated entities.